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Validation of a single-pass surgical trajectory to enable AAV2-hAADC infusion into brainstem and mid-brain in nonhuman primate

验证单次手术轨迹，使 AAV2-hAADC 能够输注到非人灵长类动物的脑干和中脑

基本信息

批准号：
10040048
负责人：
Krystof S Bankiewicz
金额：
$ 42.9万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10040048
关键词：
3-Dimensional Ablation Acids Adverse effects Adverse event Affect Amino Acids Annual Reports Area Awareness Basal Ganglia Bilateral Biochemical Brain Brain Diseases Brain Stem Cannulas Carboxy-Lyases Caregivers Cell Nucleus Child Childhood Chronic Clinical Clinical Research Clinical Trials Cohort Analysis DOPA decarboxylase Data Deficiency Diseases Deposition Disease Dopamine Dopamine Agonists Dyskinetic syndrome Dystonia Emotional Enzymes Evaluation Gene Delivery Gene Expression Genes Genetic Diseases Goals Homovanillic Acid Human Hydroxyindoleacetic Acid Hypokinesia Impaired cognition Impairment Infusion procedures Inherited Intervention Levodopa Life Limbic System Medical Midbrain structure Muscle hypotonia Mutation Neurologic Neurologic Symptoms Neurotransmitters Norepinephrine Operative Surgical Procedures Outcome Study Pathologic Pathway interactions Patients Procedures Protocols documentation Public Health Research Safety Serious Adverse Event Serotonin Site Sleep disturbances Societies Structure Substantia nigra structure Symptoms System Testing Therapeutic Time Treatment Efficacy Validation Ventral Tegmental Area Viral Vector Writing aromatic L-amino acid decarboxylase deficiency base burden of illness cohort cost dorsal raphe nucleus experimental study gene therapy improved loss of function mutation monoamine motor symptom nervous system disorder nonhuman primate noradrenergic pars compacta programs recessive genetic trait recruit vector

项目摘要

PROJECT SUMMARY/ABSTRACT Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare pediatric genetic disorder in which mutations in the DOPA decarboxylase gene (DDC) result in a non-functional AADC enzyme that causes the ablation of dopamine and serotonin synthesis. Affected children suffer prominent motor symptoms, including hypokinesia, hypotonia, oculogyric crises and dystonia, as well as emotional lability, sleep disturbance and cognitive impairment. Patients derive little symptomatic benefit from currently available medical therapies. Our long-term goal is to provide a therapeutic approach to eliminate the neurological signs and symptoms of the disease by increasing the AADC levels via localized infusion of a viral vector (AAV2) encoding human AADC into affected nuclei in the brain. In our current exploratory clinical study (NCT02852213), we have treated 9 patients with AADC deficiency with a single bilateral infusion into the pre-nigral region to restore normal dopamine synthesis in the basal ganglia and limbic system. Preliminary evaluations from cohorts 1 and 2 have proven this approach to be safe with only mild and transient dyskinesia about one month and a half after surgery. Marked reduction or elimination of oculogyric crises has been observed. Biochemical analyses showed an increase in dopamine metabolite homovanillic acid (HVA), a slight reduction of 3-oxymethyldopa (3-OMD) while serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA) remained unchanged in all patients. Currently, analyses of these cohorts, 24 and 12 months after surgery respectively, also showed that there have been no adverse events or serious adverse events related to the surgical procedure or the vector. The present proposal seeks to accumulate safety data in nonhuman primates in which a single cannula pass will enable vector delivery into serotonergic and noradrenergic nuclei as well as the current dopaminergic nuclei. Data from this study will be used to submit a new IND and recruit more patients for this new procedure. In our view, the proposed research will have a significant impact on public health. Although AADC deficiency is a rare pediatric disease, the burden to caregivers and the cost to society is large over the life of the patients not to mention the plight of the patients themselves. In the larger sense, projects like this will continue to enhance our ability to treat inherited neurological diseases.

项目总结/文摘